The following description of the background of the invention is provided to aid in understanding the invention, but is not admitted to be, or to describe, prior art to the invention. All publications are incorporated by reference in their entirety.
9-(2-phosphonylmethoxyethyl)adenine (PMEA), (R)-9-(2-phosphonyl-methoxypropyl)adenine (PMPA) and related analogues (U.S. Pat. No. 4,808,716; U.S. Pat. No. 5,142,051) are phosphonic acids that exhibit antiviral activity, including activity against hepatitis B and HIV (De Clercq et al., Antiviral Res. 8: 261–7(1987); Balzarini et al., Biochem Biophys. Res. Commun. 219(2): 337–41(1996)). The dipivaloyloxy methylene ester of PMEA (“BisPOM PMEA”) is in clinical trials for the treatment of hepatitis B (Benhamou et al., Lancet 358(9283): 718–23 (2001)). In addition, some studies have shown that these compounds also show anticancer activity (Murono et al., Cancer Res. 61(21): 7875–7(2001)).
Compounds containing phosphonic acids and their salts are highly charged at physiological pH and therefore frequently exhibit poor oral bioavailability, poor cell penetration and limited tissue distribution (e.g., CNS). In addition, these acids are also commonly associated with several other properties that hinder their use as drugs, including short plasma half-life due to rapid renal clearance, as well as toxicities (e.g., renal, gastrointestinal, etc.) (e.g., Bijsterbosch et al., Antimicrob Agents Chemother. 42(5): 1146–50 (1998)). Cyclic phosphonate esters have also been described for PMEA and related analogues. The numbering for these cyclic esters is shown below:
Unsubstituted cyclic 1′,3′-propanyl esters of PMEA were prepared but showed no in vivo activity. EP 0 481214 B1 discloses examples of cyclic prodrugs of PMEA wherein the 1′ and 3′ positions are unsubstituted. The application and a subsequent publication by the inventors (Starrett et al., J. Med. Chem. 37:1857–1864 (1994)) further disclose their findings with the compounds, namely that these compounds showed no oral bioavailability and no biological activity. The compounds were shown to be unstable at low pH, e.g., the cyclic 2′,2′-difluoro-1′,3′-propane ester is reported to be hydrolytically unstable with rapid generation of the ring-opened monoester.